HPV Vaccine: When Too Old Is Still Quite Young
HPV Vaccine: When Too Old Is Still Quite Young
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Administration of the quadrivalent HPV vaccine to women older than age 26 reduces their chance of developing HPV-related disease if they are not already infected by one of the strains.
Source: Muñoz, N, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: A randomised, double-blind trial. Lancet 2009;373:1949-1957.
Women aged 24-45 years with no history of genital warts or HPV-related cervical disease received either the quadrivalent HPV vaccine (n = 1911) or placebo vaccine (n = 1908) in a multicenter, international, parallel group, randomized, placebo-controlled, double-blind study. The study assessed 2 primary efficacy endpoints: the presence of cervical and/or external genital disease due to HPV 6, 11, 16, and/or 18; and disease due to HPV 16 or 18 alone. To be positive, a subject needed to demonstrate a persistent HPV infection caused by one of the subtypes for 6 months or longer duration at regular follow-up visits of up to 48 months. The primary efficacy analyses were done in a per-protocol (received all 3 doses of the vaccine at 1 day, 1 month, and 6 months) population, but intention-to-treat analyses were also performed.
In the per-protocol population, efficacy against disease or in-fection related to HPV 6, 11, 16, and 18 was 90.5% (95% confidence interval [CI], 73.7%-97.5%); only 4 of 1615 women in the vaccine group compared with 41 of 1607 in the placebo group showed evidence of infection with 1 of the viral types. For disease or infection related to HPV 16 or 18 alone, the protection was similar (83.1%; 95% CI, 50.6%-95.8%), with 4 of 1601 (active vaccine) and 23 of 1579 (placebo) cases. Less robust protection was noted in the intention-to-treat population, with a 30.9% (95% CI, 11.1%-46.5%) reduction in HPV 6, 11, 16, and 18 infections, and a nonstatistically significant 22.6% (CI, -2.9% to 41.9%) decrease in HPV 16 and 18 injections. Importantly, there were no vaccine-related serious adverse events.
Commentary
Cervical cancer is a dreadful disease that has fortunately become uncommon in the United States due to extensive surveillance techniques. This surveillance is accepted matter-of-factly by most women, with the ritual of the annual exam and pap smear a rite of passage and an expectation of quality health care. A positive pap screen leads to a referral for colposcopy. While HPV testing of liquid-prep paps has reduced the number of referrals to colposcopy, large numbers of women continue to endure the discomfort and anxiety associated with the exam, the biopsies, possible excision of pre-invasive cervical disease, and need for close follow-up. Women accept this because they understand the alternative (developing an invasive cervical cancer) is much worse.
While these procedures save lives, most abnormal paps detect changes that will never progress to invasive cervical cancer. The elucidation of the relationship between HPV and cervical cancer and development of the quadrivalent HPV vaccine effective against the 2 most common types of oncogenic strains affecting the cervix (16 and 18) and two strains that cause external and anal HPV (6 and 11) represent one of the breakthrough developments in gynecology. The vaccine promises not only to prevent cervical cancer, but also to reduce the far greater number of women burdened by the expense and inconvenience of colposcopy and follow-up procedures for pre-invasive disease.
Randomized studies of women age 15-24 years with no evidence of prior HPV exposure have demonstrated near 100% efficacy in preventing infection and high-grade lesions due to HPV strains 6, 11, 16, and 18 following the quadravalent vaccine.1,2 The vaccine protects women with prior exposure to one of the viral types against infection with the other three types.3 Since most HPV infection is acquired within 3 years of the onset of intercourse, the public health effort has appropriately centered on delivery of the vaccine to girls and young women years before their coital debut. Following the June 8, 2006, FDA approval of the quadravalent HPV vaccine, widespread efforts have been underway to provide vaccination to girls and young women 9-26 years of age.
Clearly, vaccinating all girls before they become sexually active (e.g., age 9-12) makes the most sense. Since these young girls are not seen in our offices, we need to be loud and vocal supporters of vaccine programs in our communities and in whatever health care reform is ultimately passed. The fact that some parents and groups want to withhold this potentially life-saving vaccine from their daughters based on unfounded beliefs that this will lead to promiscuity saddens and disappoints me. I grew up in Portland drinking the pure Bull Run water from Mt. Hood, and developed cavities in every tooth. To this day, we still resist fluoridation of our municipal water supply, but fluoride supplements are provided routinely to children by pediatricians and in schools. As a result, my children have never had a cavity. For my daughter's generation, a referral for colposcopy should be as rare.
Catch-up vaccination is currently recommended only in women age 26 and younger with no evidence of disease. In the Future II Study in Iceland, sexually active women ages 18-19 with no history of an abnormal pap who were randomized to active quadravalent vaccine were more likely to benefit from vaccination than women ages 20-23.4 Similarly, women older than age 26 in the Muñoz study that were not infected with 1 of the 4 strains at baseline showed the most benefit from the vaccine. Although vaccination of women infected with either HPV 16 or 18 at baseline will protect them against developing infection from the other strain, the Muñoz study did not measure progression to high-grade squamous lesions or cervical cancer. Therefore, there was no evidence of a clinical benefit (e.g., reduction in colposcopy exams, cervical biopsies, or treatment) for previously infected women.
So who to vaccinate? Given the expense of the vaccine, a sound public health policy would put our limited dollars and vaccine doses to work in the group where they should do the most good: young women and girls. Clinicians should redouble their efforts to ensure that all girls in their communities receive the vaccine before their first intercourse (preferably before the age of 12) and continue to recommend catch-up vaccination for women younger than age 26 recognizing that the benefits may be less. The Muñoz study shows that catch-up vaccination of older women will produce similar results.
If a woman 26 or older presents and requests vaccination, review risk factors and individualize your approach. I would not recommend vaccination of a patient with a prior positive HPV test, or a pap showing a low- or high-grade lesion as there is no evidence that this will influence her long-term need for colposcopy or risk of cervical cancer. For most married women older than age 26, the value of HPV vaccination will be limited. While viral DNA was recovered from only 8% of subjects in the Muñoz study, almost one-third showed serologic evidence of past HPV infection with 6, 11, 16, or 18.
On the other hand, results from the Muñoz study suggest that a 30-year-old single woman with a negative history will benefit from vaccination. Women in a committed relationship are not at risk for acquiring a new HPV strain. Still, about 40% of marriages in the United States end in divorce, and a new partner could potentially lead to infection. A request for vaccination might indicate a concern about the future of the marriage, so we need to listen to what our patient is telling us.
References
- Garland SM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-1943.
- Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-1927.
- Future II Study Group. Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection. J Infect Dis 2007;196:1438-1446.
- Sigurdsson K, et al. The efficacy of HPV 16/18 vaccines on sexually active 18-23 year old women and the impact of HPV vaccination on organized cervical cancer screening. Acta Obstet Gynecol Scand 2009;88:27-35.
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